Children with attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD) are known to have elevated risk for adolescent-onset substance use disorders (SUD), and those with comorbid ADHD + ODD/CD are at greatest risk. Stimulant medications such as extended release mixed amphetamine salts (MAS?XR) and non-stimulant medications (e.g. atomoxetine or guanfacine) have established efficacy for ADHD and are also beneficial for ODD/CD. However, stimulants have direct effects on the brain reward system, and abnormal reward processing is thought to mediate addiction vulnerability. Although longitudinal studies have not shown increased SUD risk in youth with ADHD treated with stimulants, it remains unknown whether stimulants might have differential effects on reward processing in high risk (HR) vs. low risk (LR) populations. fMRI offers a cost effective method of evaluating covert effects of stimulant medications for youth with ADHD and SUD risk by examining pre- to post-treatment changes in activation in the brain reward system that predate exposure to drugs of abuse. This approach is supported by the results of studies, which indicate altered (mostly elevated) sensitivity in the reward system in youth at-risk for SUD; high activation in the reward system has in turn been linked to problem drug use. However, to date, no study has examined changes in the reward system with stimulant treatment in youth with ADHD and high vs. low risk for SUD, who have never been exposed to stimulant treatment or drugs of abuse. Such research could provide important knowledge regarding the biological basis of addiction vulnerability and guide treatment selection. Our team is in an excellent position to study differences in activation in the brain reward system during fMRI before and after treatment with MAS?XR in young children (8-12 years old) with ADHD, who are nave to both stimulant treatment and drugs of abuse, divided into LR (i.e., ADHD only) and HR (i.e., ADHD + ODD/CD) groups. We will confirm that youth with ADHD/HR status have exaggerated activation in the reward network compared to ADHD/LR youth and controls, and test competing hypotheses regarding the effects of the two medications on the brain reward system, and across the different risk groups. This protocol is innovative in its approach to study young, drug-nave children at various levels of SUD risk, and is highly significant in its use of neuroimaging to delineate possible differential effects of stimulant and non-stimulant medications on reward processing in youth with ADHD and HR vs. LR for SUD as a biomarker of treatment-related risk. This research will substantially advance our understanding of the biological basis of vulnerability for addiction, and aid in the development of treatment recommendations for youth with ADHD and varying levels of SUD risk.